WO2011077043A2 - Phenol derivatives and pharmaceutical or cosmetic use thereof - Google Patents
Phenol derivatives and pharmaceutical or cosmetic use thereof Download PDFInfo
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- WO2011077043A2 WO2011077043A2 PCT/FR2010/052871 FR2010052871W WO2011077043A2 WO 2011077043 A2 WO2011077043 A2 WO 2011077043A2 FR 2010052871 W FR2010052871 W FR 2010052871W WO 2011077043 A2 WO2011077043 A2 WO 2011077043A2
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- ylamino
- methyl
- phenol
- pyridin
- methoxy
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/20—Nitrogen atoms
Definitions
- the present invention relates to novel compounds of general formula:
- the present invention proposes to provide novel phenolic derivatives, which are powerful modulators of the androgen receptor.
- - Ri represents a C 2-6 alkyl group, C 3-7 cycloalkyl, Ci -6 alkyloxy, -S (0) m -C -6 alkyl, Ci -6 fluoroalkyl, Ci -6 fluoroalkyloxy, - (CH 2) n - C 3 -9 cycloalkyl, - (CH 2) n -C 3 -9 cycloalkyl, C 2-6 alkyl-OH, - (CH 2) n -C 6 alkyloxy, - (CH 2) n -Ci- 6 fluoroalkyl , - (CH 2) p-0-Ci -6 fluoroalkyl, COR, CN, N0 2, NR 8 Rg, halogen, a phenyl or heteroaryl group containing either a) 1 to 4 nitrogen atoms or b) an oxygen atom or sulfur and 1 or 2 nitrogen atoms. These phenyl and heteroaryl groups may be optionally substituted with
- R 2 and R 3 are identical or different and represent a hydrogen atom or an alkyl dg group, C3-9 cycloalkyl, Ci -6 fluoroalkyl, - (CH 2) -C 3-9 cycloalkyl, -C 2- 6 alkyl-OH, - (CH 2) -C -6 alkyloxy, - (CH 2) -C 3-7 cycloalkyl, - (CH 2) -Ci -6 fluoroalkyl, -
- the groups R 2 and R 3 may form, with the carbon atom carrying them, a C 3-9 cycloalkyl group or a heterocycle such as tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydro-1-oxy-thiopyran or tetrahydro-1, 1-dioxy. thiopyran.
- R 4, R 5, R 6, R 7 are identical or different and represent either hydrogen or a Ci -6 alkyl, C 3-7 cycloalkyl, Ci -6 alkyloxy, -S (0) s -C - 6 alkyl, Ci -6 fluoroalkyl, Ci -6 fluoroalkyloxy, - (CH 2) t -C 3-9 cycloalkyl, - (CH 2) t -C 3-9 cycloalkyl, -C -OH -6 alkyl, - ( CH 2) t -Ci- 6 alkyloxy, - (CH 2) t -Ci- 6 fluoroalkyl, - (CH 2) u -0-Ci-6 fluoroalkyl, COR d, CN, NR 8 R 9 ', or halogen or a phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulfur atom and 1 or 2 nitrogen atom,
- X represents CH or N
- - Y represents either a nitrogen atom or a carbon atom substituted with a Ci -6 alkyl, C 3-7 cycloalkyl, Ci -6 alkyloxy, -S (0) v -Ci- 6 alkyl, Ci -6 fluoroalkyl, C1-6 fluoroalkyloxy, - (CH 2) iC 3-9 cycloalkyl, - (CH 2) iC 3-9 cycloalkyl, Ci -6 alkyl-OH, - (CH 2) i-Ci -6 alkyloxy, - ( CH 2) i-Ci -6 fluoroalkyl, - (CH 2) w -0-Ci -6 fluoroalkyl, COR e, CN, NR 10 Rn, N0 2, hydrogen or halogen or a phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulfur atom and 1 or 2 nitrogen atoms.
- R a, R d and R e are identical or different and represent a Ci -6 alkyl, Ci -6 alkyloxy or NR 12 R 13,
- R b and R c are identical or different and represent halogen, Ci -6 alkyl, C 3-7 cycloalkyl, Ci -6 alkyloxy, -S (0) j -C -6 alkyl, Ci -6 fluoroalkyl, Ci -6 fluoroalkyloxy, - (CH 2) iC 3-7 cycloalkyl, OH, - (CH 2) iC 3-7 cycloalkyl, Ci -6 alkyl-OH, - (CH 2) i- Ci -6 alkyloxy, - ( CH 2) i-Ci -6 fluoroalkyl, - (CH 2) z -0-Ci -6 fluoroalkyl, COR, CN, or NR 14 R 15
- R 8 and R 8 ' are identical or different and represent a Ci -6 alkyl, C 3-7 cycloalkyl, - (CH 2) f -C 3-7 cycloalkyl or - (CH 2) f -C -6 fluoroalkyl .
- - R 9, R 9 ', R 10, Ru, Ri2, Ri3, R 4 and R 15 are identical or different and represent a hydrogen atom, C i -6 alkyl, C 3-7 cycloalkyl, - (CH 2) g -C 3 -7 cycloalkyl or - (CH 2) g -C 6 fluoroalkyl.
- the groups R 8 and R 9 may form with the nitrogen atom which carries them a heterocycle such as: azetidine, pyrolidine, piperidine, azepane, morpholine or piperazine.
- the groups R 8 'and R 9 - can form with the nitrogen atom which carries them a heterocycle such as: azetidine, pyrolidine, piperidine, azepane, morpholine or piperazine.
- the R10 and Ru groups may form with the nitrogen atom which carries them a heterocycle such as: azetidine, pyrolidine, piperidine, azepane, morpholine or piperazine.
- R12 and R 13 may form with the nitrogen atom which carries them a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
- R 4 and R 15 may form with the nitrogen atom which carries them a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
- p, q, u, w and z are different or identical and are equal to 2, 3 or 4 as well as their pharmaceutically acceptable salts, solvates or hydrates and their conformers or rotamers.
- the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as a mixture of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof including racemic mixtures are part of the invention.
- the compounds of formula (I) may exist in the form of a base or of addition salts with acids. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids that are useful, for example for the purification or the isolation of the compounds of formula (I) are also part of the invention.
- These acids may be for example picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartric acid, a mandelic acid or a camphosulphonic acid, and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulphonate, paratoluenesulphonate.
- physiologically salts acceptable see Handbook of Pharmaceutical Salts: Properties, Selection and Use of Stahl and
- the solvates or hydrates can be obtained directly at the end of the synthesis process, the compound (I) being isolated in the form of a hydrate, for example a mono or hemihydrate or solvate of the reaction solvent or of purification.
- b and c can take values from 1 to 9, a carbon chain of b to c carbon atoms, for example Ci- 6 a carbon chain may have 1 to 6 carbon atoms
- Ci -6 alkyl represents a carbonaceous chain of 1 to 6 carbon atoms, linear or branched, preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl , pentyl, hexyl
- cycloalkyl an optionally branched cyclic saturated carbon chain containing from 3 to 7 carbon atoms.
- a C 3-7 cycloalkyl group represents a carbon chain of 3 to 7 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- heterocycle a cyclic or bicylic hydrocarbon chain, saturated or unsaturated, comprising one or more heteroatoms chosen from O, S and N,
- heteroaryl an aromatic heterocycle, preferentially a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazolyl, isooxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or imidazolyl group;
- alkylthio a -S-alkyl group
- fluoroalkyl an alkyl group in which one or more hydrogen atoms have been replaced by a fluorine atom
- fluoroalkyloxy an alkyloxy group in which one or more hydrogen atoms have been replaced by a fluorine atom
- X represents CH and Y represents a carbon atom substituted by one of the groups as defined above and preferably a methyl group, ethyl, isopropyl, cyclopropyl, CF 3 , CONH 2 , CO 2 CH 3 , CO 2 CH 2 CH 3 , CN, NO 2 , SCH 3 , SCH 2 CH 3! a hydrogen atom, a halogen, OCF 3 , OCH 3 , OCH 2 CH 3 or OCH (CH 3 ) 2 .
- the invention also relates to a process for preparing the compounds of general formula (I).
- the compounds of formula (I) can be prepared by one of the three methods described in Scheme 1 below and optionally supplemented by one or more reactions as described in Scheme 2.
- Diagram 1
- the phenol compounds of formula (I) in which R 1, R 2 , R 3, R 4 , R 5 , R 6, R 7, X and Y are as defined above can be prepared by a reductive amination reaction between an aldehyde or a benzyl ketone (II) and an amine (III) in the presence of a reducing agent, as for example and in a nonlimiting manner, sodium triacetoxyborohydride, according to Method 1 illustrated in Scheme 1 and by analogy, for example, to the reactions described in Org. Pro. R. & D. (2006) 971-1031.
- a reducing agent as for example and in a nonlimiting manner, sodium triacetoxyborohydride
- the phenolic compounds of formula (I) can be prepared by reaction between heterocycles (V) having a leaving group and benzyl amines in the presence of a base such as, but not limited to, 1,8-diazabicyclo [5.4.0 undec-7-ene, for example in a solvent such as dimethylsulfoxide and as described by Method 1b of Scheme 1.
- a base such as, but not limited to, 1,8-diazabicyclo [5.4.0 undec-7-ene, for example in a solvent such as dimethylsulfoxide and as described by Method 1b of Scheme 1.
- leaving group is meant a group well known to those skilled in the art such as non-limiting way, a halogen, a mesylate, a tosylate or a triflate.
- the third method for preparing the phenolic compounds of formula (I) consists in reducing amide intermediates (VII) by a hydride-donor reagent such as, in a non-limiting manner, lithium aluminum hydride as illustrated by Method 1c of Scheme 1.
- a hydride-donor reagent such as, in a non-limiting manner, lithium aluminum hydride as illustrated by Method 1c of Scheme 1.
- These amide intermediates can be prepared by reaction between, for example and non-limitingly, an acyl chloride (VI) and an amine (III) in pyridine.
- the acyl chlorides (VI) are prepared from the acids according to techniques well known to those skilled in the art, for example at reflux in thionyl chloride.
- Certain compounds having a sulphoxy (X) or sulphone (XI) group may optionally be prepared by oxidation of the thio ether intermediate (IX) as described in Scheme 2 according to Method 2a.
- the oxidation may, for example, and non-limitingly, be carried out by the oxone.
- the thio ether intermediate (IX) may be prepared from compounds (VIII) having a leaving group such as, but not limited to, a chlorine atom, by reaction with a thiolate in dimethylsulfoxide.
- Certain compounds containing an ether group may optionally be prepared by reaction of the intermediate (VIII) with the corresponding alcohol such as, for example, without limitation, methanol in the presence of a base such as sodium hydroxide, optionally by Microwave heating and as described in Scheme 2 according to Method 2b.
- a base such as sodium hydroxide
- the functional groups optionally present in the reaction intermediates used in the process may be protected, either permanently or temporarily, by protecting groups which ensure a unambiguous synthesis of the expected compounds.
- the protection and deprotection reactions are carried out according to techniques well known to those skilled in the art.
- temporary protective group of amines, alcohols or carboxylic acids is meant protective groups such as those described in "Protective Groups in Organic Chemistry", ed McOmie JWF, Plenum Press, 1973, in “Protective Groups in Organic Synthesis", 2 nde edition, Greene TW and Wuts PGM, ed. John Wiley and Sons, 1991 and in “Protecting Groups", Kocienski PJ, 1994, Georg Thieme Verlag.
- the products object of the present invention are endowed with interesting pharmacological properties; in particular, they have been shown to modulate the androgen receptor activity.
- Tests given in the experimental part illustrate this modulatory activity of the androgen receptor.
- the products of the present invention exhibit antagonistic or partial or total agonist activities. Because of this activity, the products of the invention can be used as medicaments in humans or animals.
- the products of general formula (I) of the invention find their cosmetic use of a compound for body or hair hygiene.
- the products of general formula (I) of the invention also find their use in the treatment of hirsutism, acne, seborrhea, the oily skin of andro-genic alopecia, hyperpilosity or hirsutism, , and they can be used for the manufacture of a medicament for preventing and / or treating hirsutism, androgenic alopecia, hyperpilosity, atopic dermatitis, disorders of the sebaceous gland such as hyperseborrhoea, acne, oily skin or seborrheic dermatitis.
- the products of formula (I) can therefore be used in dermatology: they can be used alone or in combination.
- reductase such as (5alpha, 17beta) -N-1,1-dimethylethyl-3-oxo-4-aza-androst-1-ene 17-carboxamide (or finasteride Merck, 13th edition) or azelaic acid or a blocking agent androgen receptors for the treatment of acne, alopecia or hirsutism, or with a hair growth stimulating product such as Minoxidil for the treatment of alopecia.
- an antibiotic product such as derivatives of azelaic acid, fusidic acid, erythromycin or with a derivative of retinoids such as tretinoin for the treatment of acne
- reductase such as (5alpha, 17beta) -N-1,1-dimethylethyl-3-oxo-4-aza-androst-1-ene 17-carboxamide (or finasteride Merck, 13th edition) or azelaic acid or a blocking agent androgen receptors
- the subject of the present invention is also, as a medicament, the compounds of formula (I) as described above, as well as their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and / or hydrates.
- the preparation of active compounds of formula (I) according to the invention are given below, as well as results of biological activity of such compounds.
- This intermediate is prepared according to the procedure described for 6-ethoxy-pyridin-2-ylamine, replacing the ethanol with isopropanol.
- the expected product is obtained in the form of a colorless oil.
- Examples 2 to 12 are described in Table 1 below.
- the compounds are synthesized according to the procedure above, replacing the starting products 1 and 2 mentioned in Example 1 by the products mentioned in Table 1.
- Examples 14 to 18 are described in Table 2 below.
- the compounds are synthesized according to the procedure above, replacing the starting materials 3 and 4 mentioned in Example 13 by the products mentioned in Table 2.
- Example 19 2- (6-Methoxy-pyrazin-2-ylamino) -methyl-phenol Synthesis According to Scheme 2, Method 2b In a microwave tube, 363 mg (1.29 mmol) of 2 - [(6-bromo-pyrazin-2-ylamino) -methyl] -phenol, prepared as described previously in Example 12, were added to which 3 ml of methanol and 103mg (2.58mmol, 2eq) of sodium hydroxide. The reaction medium is then heated for 30 min in the microwave oven at 150 ° C and then diluted with 50ml of ethyl acetate.
- This compound is prepared according to the procedure described for Example 19 from 2 - [(2-chloro-pyrimidin-4-ylamino) -methyl] -phenol. 2 - [(2-Methoxy-pyrimidin-4-ylamino) -methyl] -phenol is obtained in the form of a white solid.
- This compound is prepared according to the procedure described for example 19 above from 2 - [(2-chloro-6-methyl-pyrimidin-4-ylamino) -methyl] -phenol.
- Example 23 2- (6-Methanesulfinyl-pyridin-2-ylamino) -methyl-phenol 160 mg (0.66 mmoles) of 2 - [(6-methanesylfanyl-pyridin-2-ylamino) -methyl] phenol and 406 mg are mixed (0.66 mmol, 1 eq) of oxone in 20 ml of dioxane. After stirring for one hour at ambient temperature, the reaction medium is heated at 90 ° C. for 4 hours. After returning to ambient temperature, the reaction medium is diluted with 50 ml of ethyl acetate and then washed twice with 50 ml of water.
- the reaction medium is diluted with 100 ml of ethyl acetate, the aqueous phase is extracted and washed with 50 ml of ethyl acetate.
- the organic phases are extracted twice with 50 ml of ethyl acetate and then washed with twice 50 ml of water.
- the organic phases are concentrated to dryness and the residue is purified by chromatography on silica eluting with a mixture of heptane / ethyl acetate (1/1).
- 2-Hydroxy-N- (6-methoxy-pyridin-2-yl) -3-methylbenzamide is obtained as a white solid.
- EXAMPLE 26 Biological Tests
- the compounds according to the invention exhibit inhibitory properties of AR type receptors.
- This AR receptor inhibitory activity is measured in a transactivation assay by dissociation constants KdR (rest), KdA (active) and Kdapp (apparent) according to the method disclosed in J. Molecular Biology (1965), 12 (1). ), 88-118, Monod J. et al.
- inhibitor of ARs-type receptors is meant according to the invention any compound which has a dissociation constant Kdapp of less than or equal to 1 ⁇ , and a KdR / KdA ratio ⁇ 10, in a transactivation test.
- the preferred compounds of the present invention have a dissociation constant less than or equal to 500 nM, and advantageously less than or equal to 100 nM.
- the transactivation test is carried out in the PALM (PC3 Androgen receptor Luciferase MMTV) cell line, which is a stable transfectant containing the plasmids PMMTV-neo-Luc (reporter gene) and pSG5puro-AR.
- PALM PC3 Androgen receptor Luciferase MMTV
- crossed curves of the product to be tested against a reference agonist, methyltrienolone, are carried out in a 96-well plate.
- the test product is used at 10 concentrations and the reference agonist at 7 concentrations.
- a Kdapp of 40 nM is obtained for the compound (1)
- a Kdapp of 2 nM is obtained for the compound (2)
- an Kdapp of 8 nM is obtained for the compound (19)
- a Kdapp of 1000 nM is obtained for the compound (18)
- a Kdapp of 200 nM is obtained for the compound (4).
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Abstract
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Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
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MX2012007098A MX2012007098A (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof. |
BR112012015392A BR112012015392A2 (en) | 2009-12-23 | 2010-12-22 | "compound and cosmetic use of a compound" |
CA2784822A CA2784822A1 (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
RU2012130958/04A RU2540858C2 (en) | 2009-12-23 | 2010-12-22 | New phenol derivatives and their pharmaceutical or cosmetic application |
AU2010334641A AU2010334641B2 (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
CN2010800645745A CN102762537A (en) | 2009-12-23 | 2010-12-22 | Novel phenol derivatives and pharmaceutical or cosmetic use thereof |
KR1020127018945A KR101450172B1 (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
US13/519,100 US9050266B2 (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
JP2012545395A JP5581399B2 (en) | 2009-12-23 | 2010-12-22 | Novel phenol derivatives and their use as pharmaceuticals or cosmetics |
EP10808915.2A EP2516398B1 (en) | 2009-12-23 | 2010-12-22 | Phenolic derivatives, and their pharmaceutical or cosmetic use |
US14/707,711 US9505720B2 (en) | 2009-12-23 | 2015-05-08 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
US15/299,108 US20170037015A1 (en) | 2009-12-23 | 2016-10-20 | Novel phenol derivatives and pharmaceutical or cosmetic use thereof |
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US28215309P | 2009-12-23 | 2009-12-23 | |
FR0959475 | 2009-12-23 | ||
US61/282,153 | 2009-12-23 | ||
FR0959475A FR2954317B1 (en) | 2009-12-23 | 2009-12-23 | NOVEL PHENOLIC DERIVATIVES, AND THEIR PHARMACEUTICAL OR COSMETIC USE |
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US13/519,100 A-371-Of-International US9050266B2 (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
US14/707,711 Continuation US9505720B2 (en) | 2009-12-23 | 2015-05-08 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
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WO2011077043A3 WO2011077043A3 (en) | 2011-08-18 |
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PCT/FR2010/052871 WO2011077043A2 (en) | 2009-12-23 | 2010-12-22 | Phenol derivatives and pharmaceutical or cosmetic use thereof |
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US (3) | US9050266B2 (en) |
EP (1) | EP2516398B1 (en) |
JP (1) | JP5581399B2 (en) |
KR (1) | KR101450172B1 (en) |
CN (1) | CN102762537A (en) |
AU (1) | AU2010334641B2 (en) |
BR (1) | BR112012015392A2 (en) |
CA (1) | CA2784822A1 (en) |
FR (1) | FR2954317B1 (en) |
MX (1) | MX2012007098A (en) |
RU (1) | RU2540858C2 (en) |
WO (1) | WO2011077043A2 (en) |
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US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
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US10774064B2 (en) | 2016-06-02 | 2020-09-15 | Cadent Therapeutics, Inc. | Potassium channel modulators |
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Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2954315B1 (en) * | 2009-12-23 | 2012-02-24 | Galderma Res & Dev | NOVEL PHENOLIC DERIVATIVES, AND THEIR PHARMACEUTICAL OR COSMETIC USE |
CN113966217A (en) * | 2019-06-14 | 2022-01-21 | 达萨玛治疗公司 | SARM1 inhibitors |
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- 2010-12-22 BR BR112012015392A patent/BR112012015392A2/en not_active IP Right Cessation
- 2010-12-22 RU RU2012130958/04A patent/RU2540858C2/en not_active IP Right Cessation
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EP2516398A2 (en) | 2012-10-31 |
RU2540858C2 (en) | 2015-02-10 |
JP2013515705A (en) | 2013-05-09 |
FR2954317B1 (en) | 2012-01-27 |
MX2012007098A (en) | 2012-07-20 |
JP5581399B2 (en) | 2014-08-27 |
US20140275536A1 (en) | 2014-09-18 |
US20160115132A1 (en) | 2016-04-28 |
US9505720B2 (en) | 2016-11-29 |
US9050266B2 (en) | 2015-06-09 |
AU2010334641A1 (en) | 2012-08-09 |
EP2516398B1 (en) | 2018-03-21 |
KR20120096094A (en) | 2012-08-29 |
CA2784822A1 (en) | 2011-06-30 |
WO2011077043A3 (en) | 2011-08-18 |
CN102762537A (en) | 2012-10-31 |
KR101450172B1 (en) | 2014-10-14 |
US20170037015A1 (en) | 2017-02-09 |
RU2012130958A (en) | 2014-01-27 |
BR112012015392A2 (en) | 2017-04-25 |
AU2010334641B2 (en) | 2014-06-12 |
FR2954317A1 (en) | 2011-06-24 |
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